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metabolism
amino acid transporter SLC-36.1 and PPK-3 function in the same genetic pathway, and they directly interact with one another. The SLC-36.1-PPK-3 axis is essential for autophagic lysosome reformation (ALR)
additional information
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Gly867 and Gly1870 are required for the functioning of CgFab1
malfunction
a loss of enzyme function causes the release of late endosomal proteins, Ara7, and SNX1 from the endosome membrane. Downregulation of FAB1A/B or YM201636 inhibitor treatment affects the auxin distribution and and alteration of PIN2 localization in root cells. FAB1 knockdown causes relocation of the basal polarity of PIN2 in young root cortical cells
malfunction
enzyme inhibition reduces contraction- and AICAriboside (5-amino-4-imidazolecarboxamide riboside)-stimulated glucose uptake. PIKfyve knockdown in C2C12 myotubes reduced AICAriboside-stimulated glucose transport
malfunction
the vacuolation phenotype in cultured Vps34 (EC 2.7.1.137)-deficient podocytes is caused by the absence of a substrate for the Vps34 downstream effector PtdIns 3-phosphate 5-kinase, which phosphorylates Vps34-generated 1-phosphatidyl-1D-myo-inositol 3-phosphate to produce + 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate. PtdIns 3-phosphate 5-kinase perturbation and 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate reduction result in massive membrane vacuolation along the endosomal system. Genetic deletion of the enzyme in endocytically active proximal tubular cells results in the development of large cytoplasmic vacuoles caused by arrested endocytic traffic progression at a late-endosome stage, while deletion of the enzyme in glomerular podocytes does not significantly alter the endosomal morphology, even in age 18-month-old mice
malfunction
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CgFAB1 disruption impaires vacuole homeostasis and actin organization, and the F-actin stabilizing compound jasplakinolide rescues azole toxicity in cytoskeleton defective-mutants including the Cgfab1DELTA mutant. The actin depolymerization factor CgCof1 binds to multiple lipids including phosphatidylinositol 3,5-bisphosphate. CgCof1 distribution along with the actin filament-capping protein CgCap2 is altered upon both CgFAB1 disruption and fluconazole exposure. Actin polymerization inhibition renders fluconazole fully and partially fungicidal in azole-susceptible and azole-resistant Candida glabrata clinical isolates, respectively, thereby, underscoring the role of fluconazole-effectuated actin remodeling in azole resistance. MDR genes are activated in the Cgfab1DELTA mutant upon fluconazole exposure. Fluconazole-treated wild-type and Cgfab1DELTA cells display a 1.5fold increased efflux of the MDR pump substrate rhodamine 6G
malfunction
loss of PPK-3, the Caenorhabditis elegans homologue of the PtdIns3P 5-kinase PIKfyve, causes accumulation of phagolysosomal vacuoles that are defective in phagocytic lysosome reformation (PLR). Loss of slc-36.1 and ppk-3 causes strong defects in autophagic lysosome reformation in adult animals. Ppk-3(n2668) strong loss-of-function mutants embryos contain many vacuolar structures of different sizes, a subset of which are positive for both LAAT-1::GFP and HIS-24::mCh, indicating that they are phagolysosomes. The double mutants of slc-36.1(yq110) with ppk-3(n2668) contain enlarged autolysosomes similar to ppk-3(n2668) single mutants
malfunction
Ste12PIKFYVE-deficient mutants are unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline) growth conditions. Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes), neither a block to autophagy or mutants that independently have enlarged vacuoles has any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE-deficient mutants reduces cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. Ste12 mutants display increased Torin1 (TOR inhibitor) sensitivity. No major impact on TORC1 or TORC2 activity is observed in the ste12-deficient mutants. Advancement of cell division is markedly compromised in ste12PIKFYVE.W1037STOP cells as a consequence of a reduction in the efficiency with which mitosis is advanced by the stress. Thus, ste12PIKFYVE-W1037STOP cells are deficient in their nitrogen stress response. Rapamycin rescues both the inability to advance mitosis and reduce cell size at division, suggesting that Ste12 may acts upstream of TORC1. ste12PIKFYVE-W1037STOP autophagy defect is unlikely to account for the inability to control size after nitrogen stress
malfunction
the intracellular trafficking of pathogens, Zaire EBOV GP (VSV-MeGFPZEBOV) and SARS-CoV-2 S Wuhan-Hu-1 strain (VSV-eGFP-SARS-CoV-2), is elicited by inhibition of PIKfyve kinase via apilimod and vacuolin-1, small-molecule inhibitors of the main endosomal phosphatidylinositol-3-phosphate/phosphatidylinositol 5-kinase, PIKfyve
malfunction
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Ste12PIKFYVE-deficient mutants are unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline) growth conditions. Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes), neither a block to autophagy or mutants that independently have enlarged vacuoles has any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE-deficient mutants reduces cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. Ste12 mutants display increased Torin1 (TOR inhibitor) sensitivity. No major impact on TORC1 or TORC2 activity is observed in the ste12-deficient mutants. Advancement of cell division is markedly compromised in ste12PIKFYVE.W1037STOP cells as a consequence of a reduction in the efficiency with which mitosis is advanced by the stress. Thus, ste12PIKFYVE-W1037STOP cells are deficient in their nitrogen stress response. Rapamycin rescues both the inability to advance mitosis and reduce cell size at division, suggesting that Ste12 may acts upstream of TORC1. ste12PIKFYVE-W1037STOP autophagy defect is unlikely to account for the inability to control size after nitrogen stress
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malfunction
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Ste12PIKFYVE-deficient mutants are unable to advance the cell cycle to reduce cell size after a nitrogen downshift to poor nitrogen (proline) growth conditions. Ste12PIKFYVE mutants have enlarged vacuoles (yeast lysosomes), neither a block to autophagy or mutants that independently have enlarged vacuoles has any impact upon nitrogen control of mitotic commitment. The addition of rapamycin to Ste12PIKFYVE-deficient mutants reduces cell size at division to suggest that Ste12PIKFYVE possibly functions upstream of TORC1. Ste12 mutants display increased Torin1 (TOR inhibitor) sensitivity. No major impact on TORC1 or TORC2 activity is observed in the ste12-deficient mutants. Advancement of cell division is markedly compromised in ste12PIKFYVE.W1037STOP cells as a consequence of a reduction in the efficiency with which mitosis is advanced by the stress. Thus, ste12PIKFYVE-W1037STOP cells are deficient in their nitrogen stress response. Rapamycin rescues both the inability to advance mitosis and reduce cell size at division, suggesting that Ste12 may acts upstream of TORC1. ste12PIKFYVE-W1037STOP autophagy defect is unlikely to account for the inability to control size after nitrogen stress
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physiological function
in Xenopus oocytes expressing mammalian excitatory amino acid transporter EAAT4, glutamate induces a current which is significantly enhanced by coexpression of isoform PIKfyve and glucocorticoid inducible kinase SGK1. This glutamate-induced current is significantly larger than the current in Xenopus oocytes expressing EAAT4 together with either kinase alone. Coexpression of the inactive SGK1 mutant K127N does not significantly alter glutamate-induced current in EAAT4-expressing Xenopus oocytes and abolishes the stimulation of glutamate-induced current by coexpression of isoform PIKfyve. The stimulating effect of PIKfyve is abrogated by mutation S318A in the SGK consensus sequence of PIKfyve. Coexpression of PIKfyve S318A mutant significantly blunts the stimulating effect of SGK1 on EAAT4 activity
physiological function
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PIKFYVE knockdown produces a 36% reduction in phosphatidylinositol 3,5-bisphosphate and a 13% increase in phosphatidylinositol 3-phosphate. PIKFYVE and class II phosphatidylinositol 3-kinase PI3K-C2alpha are necessary for activation of the kinase complex mechanistic target of rapamycin mTORC1 and its translocation to the plasma membrane in 3T3-L1 adipocytes. The mTORC1 component Raptor directly interacts with phosphatidylinositol 3,5-bisphosphate
physiological function
the enzyme activity is implicated in be involved in contraction/AMPK (AMP-activated protein kinase)-stimulated glucose uptake in skeletal muscle rather than insulin-stimulated glucose uptake. The enzyme is an AMPK substrate whose phosphorylation at Ser307 promotes PIKfyve translocation to endosomes for PtdIns(3,5)P2 synthesis to facilitate GLUT4 (glucose transporter 4) translocation
physiological function
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the enzyme activity is required for the stimulation of skeletal muscle glucose uptake by contraction/AMPK activation. In opossum kidney cells, wild-type, but not S307A mutant, PIKfyve is recruited to endosomal vesicles in response to AMPK activation
physiological function
the enzyme mediates endosome maturation to establish endosome-cortical microtubule interaction in Arabidopsis thaliana. The enzyme and its product, 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate, are essential for the maturation process of endosomes to mediate cortical microtubule association of endosomes, thereby controlling proper PIN-FORMED protein trafficking in young cortical and stele cells of root. The enzyme and its product mediate the late endosome maturation by recruiting endosomal effector molecules, Ara7 and SNX1, onto endosomes to establish endosome-cortical microtubule interaction
physiological function
analysis of the intracellular trafficking of pathogens elicited by inhibition of PIKfyve kinase
physiological function
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enzyme CgFab1 is implicated in azole tolerance through actin network remodeling. CgFab1 is required for vacuole homeostasis. Fluconazole induces actin cytoskeletal depolarization in a CgFab1-dependent manner, in part, through the PI 3,5-bisphosphate [PI(3,5)P2]-binding protein, CgCof1. CgFab1 is involved in response to azole, cell membrane and cell wall stress. Fluconazole-treated wild-type and Cgfab1DELTA cells display a 1.5fold increased efflux of the MDR pump substrate rhodamine 6G
physiological function
PIKFYVE is a 1-phosphatidylinositol-3-phosphate 5-kinase that is required for the production of a signalling phospholipid required for vacuole functions and endosome dynamics, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). PI(3,5)P2 is reported to be a positive regulator of TORC1 activity on the yeast vacuole, that is required for TORC1 inhibition of autophagy under nutrient-rich conditions. PIKFYVE also regulates cell type-specific activation and localization of mTORC1 in 3T3-L1 adipocytes. In humans, mutations predicted to lead to minor changes in PI(3,5)P2 levels are associated with severe neurological diseases and are implicated in the invasive behaviour of cancer cells. Ste12/Fab1 phosphatidylinositol-3-phosphate 5-kinase is required for nitrogen-regulated mitotic commitment and cell size control. Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division
physiological function
the phosphatidylinositol 3-phosphate (PtdIns3P) 5-kinase PIKfyve and the lysosomal calcium channel TRPML1 are required for endocytic lysosome reformation. PIKfyve generates phosphatidylinositol 3,5-bisphosphate, which activates TRPML1 to control lysosomal Ca2+ efflux. The SLC-36.1-PPK-3 axis is essential for ALR
physiological function
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PIKFYVE is a 1-phosphatidylinositol-3-phosphate 5-kinase that is required for the production of a signalling phospholipid required for vacuole functions and endosome dynamics, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). PI(3,5)P2 is reported to be a positive regulator of TORC1 activity on the yeast vacuole, that is required for TORC1 inhibition of autophagy under nutrient-rich conditions. PIKFYVE also regulates cell type-specific activation and localization of mTORC1 in 3T3-L1 adipocytes. In humans, mutations predicted to lead to minor changes in PI(3,5)P2 levels are associated with severe neurological diseases and are implicated in the invasive behaviour of cancer cells. Ste12/Fab1 phosphatidylinositol-3-phosphate 5-kinase is required for nitrogen-regulated mitotic commitment and cell size control. Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division
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physiological function
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PIKFYVE is a 1-phosphatidylinositol-3-phosphate 5-kinase that is required for the production of a signalling phospholipid required for vacuole functions and endosome dynamics, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P2). PI(3,5)P2 is reported to be a positive regulator of TORC1 activity on the yeast vacuole, that is required for TORC1 inhibition of autophagy under nutrient-rich conditions. PIKFYVE also regulates cell type-specific activation and localization of mTORC1 in 3T3-L1 adipocytes. In humans, mutations predicted to lead to minor changes in PI(3,5)P2 levels are associated with severe neurological diseases and are implicated in the invasive behaviour of cancer cells. Ste12/Fab1 phosphatidylinositol-3-phosphate 5-kinase is required for nitrogen-regulated mitotic commitment and cell size control. Ste12PIKFYVE is required for nitrogen-stress mediated advancement of mitosis to reduce cell size at division
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